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Colchicine for treating acute gout attacks

We reviewed the evidence about the benefits and harms of colchicine in acute gout up to April 2014 and identified two trials. One trial included 43 participants and compared high-dose colchicine (1 mg of colchicine followed by 0.5 mg every two hours until the attack resolved or participants had side effects (total dose unspecified)) to placebo. The second study included 184 participants and compared high-dose (total 4.8 mg over six hours) to low-dose colchicine (total 1.8 mg over one hour) and high or low-dose colchicine to placebo.

What is gout and what is colchicine?

Gout is a very common cause of inflammatory arthritis (pain, redness, warmth and swelling of affected joints) and is caused by urate crystals forming either within or around joints. Uric acid is a normal waste product that is usually excreted with urine. However, in the case of gout, there is either excessive production of uric acid, or the body is not able to excrete it quickly enough, or a combination of both. An attack of gout usually occurs rapidly and usually resolves within 7 to 10 days.

Colchicine is a drug that is used mainly in gout to treat an acute attack or to prevent an attack while starting uric acid-lowering therapy.

Best estimate of what happens to people with gout who use high-dose colchicine compared to a fake medication (placebo) after 32 to 36 hours:

Pain:- 52 people out of 100 who used high-dose colchicine rated their pain 50% lower compared to 24 people out of 100 who used placebo (28% absolute difference).

Side effects:- 84 people out of 100 who used high-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 22 people out of 100 who used placebo (62% absolute difference).

Inflammation (redness and swelling of the joint):

- 50 people out of 100 who used high-dose colchicine rated their inflammation 50% lower compared to 5 people out of 100 who used a placebo (45% absolute difference).

Best estimate of what happens to people with gout who use low-dose colchicine compared to a fake medication (placebo) after 32 to 36 hours:

Pain:

- 42 people out of 100 who used low-dose colchicine rated their pain 50% lower compared to 17 people out of 100 who used placebo (25% absolute difference).

Side effects:

- 26 people out of 100 who used low-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 20 people out of 100 who used placebo (6% absolute difference).

Best estimate of what happens to people with gout who use high-dose colchicine compared to low-dose colchicine after 32 to 36 hours:

Pain:

- 37 people out of 100 who used high-dose colchicine rated their pain 50% lower compared to 42 people out of 100 used low-dose colchicine (this may have happened by chance).

Side effects:

- 77 people out of 100 who used high-dose colchicine had side effects (such as diarrhoea, vomiting or nausea) compared to 26 people out of 100 who used low-dose colchicine (51% absolute difference).

We do not know how many people dropped out of the studies due to side effects, or whether they had any changes in inflammation (joint swelling/erythema/ tenderness), function of the target joint, patient global assessment or health-related quality of life, because this was not reported in the studies that compared low-dose to placebo or high-dose to low-dose colchicine.

Quality of the evidence

This review shows that in people with acute gout:

- There is low-quality evidence that treatment of acute gout with high-dose colchicine may reduce pain, swelling, redness and tenderness.

- There is low-quality evidence that high-dose colchicine may have little or no difference in decreasing pain compared to low-dose colchicine.

- There is low-quality evidence that low-dose colchicine has fewer side effects such as nausea, vomiting and diarrhoea than high-dose colchicine.

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Authors' conclusions:

Based upon only two published trials, there is low-quality evidence that low-dose colchicine is likely to be an effective treatment for acute gout. We downgraded the evidence because of a possible risk of selection and reporting biases and imprecision. Both high and low-dose colchicine improve pain when compared to placebo. While there is some uncertainty around the effect estimates, compared with placebo, high-dose but not low-dose colchicine appears to result in a statistically significantly greater number of adverse events. Therefore low-dose colchicine may be the preferred treatment option. There are no trials about the effect of colchicine in populations with comorbidities or in comparison with other commonly used treatments, such as NSAIDs and glucocorticoids.

Read the full abstract...

Background:

This is an update of a Cochrane review first published in 2006. Gout is one of the most common rheumatic diseases worldwide. Despite the use of colchicine as one of the first-line therapies for the treatment of acute gout, evidence for its benefits and harms is relatively limited.

Objectives:

To evaluate the benefits and harms of colchicine for the treatment of acute gout.

Search strategy:

We searched the following electronic databases from inception to April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2010 until 2013) and reference lists of identified studies. We searched the clinical trials register clinicaltrials.gov and the WHO trials register.

Selection criteria:

We considered published randomised controlled trials (RCTs) and controlled clinical trials (CCTs) evaluating colchicine therapy compared with another therapy (active or placebo) in acute gout. The primary benefit outcome of interest was pain, defined as a proportion with 50% or greater decrease in pain, and the primary harm outcome was study participants withdrawal due to adverse events.

Data collection and analysis:

Two authors independently screened search results for relevant studies, extracted data into a standardised form and assessed the risk of bias of included studies. We pooled data if deemed to be sufficiently clinically homogeneous. We assessed the quality of the body of evidence for each outcome using the GRADE approach.

Main results:

Two RCTs (124 participants) were included in this updated review, including one new RCT. We considered one trial to be at low risk of bias, while we considered the newly included trial to be at unclear risk of bias. Both trials included a placebo and a high-dose colchicine arm, although the colchicine regimens varied. In one trial 0.5 mg colchicine was given every two hours until there was either complete relief of symptoms or toxicity and the total doses were not specified. In the other trial a total of 4.8 mg colchicine was given over six hours. The newly identified trial also included a low-dose colchicine arm (total 1.8 mg over one hour).

Based upon pooled data from two trials (124 participants), there is low-quality evidence that a greater proportion of people receiving high-dose colchicine experience a 50% or greater decrease in pain from baseline up to 32 to 36 hours compared with placebo (35/74 in the high-dose colchicine group versus 12/50 in the placebo group (risk ratio (RR) 2.16, 95% confidence interval (CI) 1.28 to 3.65), with a number needed to treat to benefit (NNTB) of 4 (95% CI 3 to 12). However, the total number of adverse events (diarrhoea, vomiting or nausea) is greater in those who receive high-dose colchicine versus placebo (62/74 in the high-dose colchicine group versus 11/50 in the placebo group (RR 3.81, 95% CI 2.28 to 6.38), with a number needed to treat to harm (NNTH) of 2 (95% CI 2 to 5). Only one trial included reduction of inflammation as part of a composite measure comprising pain, tenderness, swelling and erythema, each graded on a four-point scale (none 0 to severe 3) to derive a maximum score for any one joint of 12. They reported the proportion of people who achieved a 50% reduction in this composite score. Based upon one trial (43 participants), there was low-quality evidence that more people in the high-dose colchicine group had a 50% or greater decrease in composite score from baseline up to 32 to 36 hours than people in the placebo group (11/22 in the high-dose colchicine group versus 1/21 in the placebo group (RR 10.50, 95% CI 1.48 to 74.38) and 45% absolute difference).

Based upon data from one trial (103 participants), there was low-quality evidence that low-dose colchicine is more efficacious than placebo with respect to the proportion of people who achieve a 50% or greater decrease in pain from baseline to 32 to 36 hours (low-dose colchicine 31/74 versus placebo 5/29 (RR 2.43, 95% CI 1.05 to 5.64)), with a NNTB of 5 (95% CI 2 to 20). There are no additional harms in terms of adverse events (diarrhoea, nausea or vomiting) with low-dose colchicine compared to placebo (19/74 and 6/29 respectively (RR 1.24, 95% CI 0.55 to 2.79)).

Based upon data from one trial (126 participants), there is low-quality evidence that there are no additional benefits in terms of the proportion of people achieving 50% or greater decrease in pain from baseline up to 32 to 36 hours with high-dose colchicine compared to low-dose (19/52 and 31/74 respectively (RR 0.87, 95% CI 0.56 to 1.36). However, there were statistically significantly more adverse events in those who received high-dose colchicine (40/52 versus 19/74 in the low-dose group (RR 3.00, 95% CI 1.98 to 4.54)), with a NNTH of 2 (95% CI 2 to 3).

No trials reported function of the target joint, patient-reported global assessment of treatment success, health-related quality of life or withdrawals due to adverse events. We identified no studies comparing colchicine to non-steroidal anti-inflammatory drugs (NSAIDs) or other active treatments such as glucocorticoids (by any route).

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